Damage to mitochondrial DNA (mtDNA) may play an important role in the aging process or in age-associated neurodegenerative diseases. Recent studies indicate that mtDNA mutations cause myopathies, are involved in an increasing number of other diseases, including diabetes, and show marked increases in some human tissues with increasing age. We have identified and quantitated a 4.8 kb and a 3.7 kb deletion in rat and mouse, respectively and shown increases with age. Liver mtDNA from 24 mo diet-restricted rats were found to have an average of 1/10 deletion-containing genomes as ad libitum fed rats. Analogous studies are underway in mice and monkeys. These data support the suggestion that oxidative damage, which is reduced in diet-restricted, longer living animals, plays a role in generation of these mutations. MtDNA damage causing these mutations may be important in muscle weakness, neurodegeneration and other age-associated changes.